The radionuclide .sup.99m Tc has excellent physical decay characteristics for application in nuclear medicine, and is readily available in a radionuclide generator system. More than 80% of all diagnostic nuclear medicine procedures in the United States now involve the administration of radiopharmaceuticals labeled with this radioisotope. The 140 keV gamma ray emitted in 89% of all disintegrations of this metastable nuclear state is well matched to the properties of modern scintillation camera systems, and the level of nonpenetrating radiation following decay gives a low absorbed radiation dose to the recipient. In turn, this means that large amounts of radioactivity can be administered leading to more reliable statistics in quantitative studies. Thus, serial monitoring also is possible with technetium. Additionally, the halflife of 6.02 hours is better matched to the length of most current studies.
The ability to assess pathologically altered myocardial morphology and function is of paramount importance given the incidence of heart disease in the population. The current methods of choice in routine nuclear medicine for studying the patency of cardiac structure and function are .sup.201 Tl as thallous chloride for perfusion, .sup.99m Tc-labeled erythrocytes for gated wall motion and ejection fraction determinations, and .sup.99m Tc-pyrophosphate for infarct-avid imaging. None of these agents, however, are useful for the study of the primary energy source of the heart under aerobic physiological conditions: i.e. the oxidation of fatty acids. See Bing et al., Am. J. Med. 16:504 (1954).
Over the last decade, considerable effort has been directed toward the synthesis of fatty-acid derivatives, labeled with gamma and positron-emitting radionuclides, in order to provide a non-invasive means of assessing regional myocardial metabolism and its pathology-related variation. See Machulla, "Radioactive Labelling of Fatty Acids for Metabolic Studies" in Lambrecht et al. (eds.), Application of Nuclear and Radiochemistry, Pergamon Press, New York (1982) at p. 325.
Much emphasis has been placed on iodinated derivatives, in which omega-substitution has been found to cause least deviation from normal biodistribution. However terminally iodinated fatty acids give high blood (background) levels because of their rapid degradation to free iodide. To overcome this problem, the use omega-iodophenyl substituted fatty acids (Machulla et al., Eur. J. Nucl. Med. 5:171 (1980)) was tried. These derivatives are metabolized to iodobenzoic or iodophenylacetic acid which is then rapidly excreted through the kidneys. Nevertheless, omega-.sup.123 I-heptadecanoic acid has been used in the clinical assessment of regional myocardial function in conjunction with an involved background-subtraction procedure. See Freundlieb et al., J. Nucl. Med. 21:1043 (1980).
Since .sup.99m Tc has near ideal physical characteristics for external imaging, several attempts have been made to prepare .sup.99m Tc-labelled fatty acids. Eckelman (Eckelman et al., J. Pharm. Sci. 64:704 (1975) and Karesh et al., J. Pharm. Sci. 66:225 (1977)) and Loberg (Loberg et al., J. Nucl. Med., 20:1181 (1979)) prepared several fatty acids omega-substituted with iminoacetate-type ligands. Fritzberg (Fritzberg et al., J. Lab. Comp. Radiopharm. 18:52 (1981)) prepared a hexa-thio ligand derivative and Livni (Livni et al., Radiopharm. II p. 487 (1979)) prepared some mercaptoacetate derivatives. Each of these ligands formed .sup.99m Tc complexes but none showed the desired myocardial specificity. The preparation of fatty acid derivatives labeled with .sup.99m Tc having high myocardial specificity is highly desirable.
Oxotechnetium (+5) bisamido bisthiolato (N.sub.2 S.sub.2) anion complexes have been reported as kidney imaging agents. See U.S. patent application Ser. No. 524,888, now U.S. Pat. No. 4,673,562, filed Aug. 19, 1983 and Jones et al., J. Nucl. Med. 23:801 (1982). The anion, oxo[N,N'-ethylenebis(2-mercapto-acetamido)]technetate (+5), i.e. [TcO(ema)].sup.-, is stable not only in vitro but also in vivo at both carrier-added (CA) and no-carrier-added (NCA) concentrations.
J. W. Brodack disclosed the complex .sup.99m Tc-oxo[N,N'-ethylene-bis(2-mercapto)-[2'-(11-carboxyundecyl)]thio-acetamid o]-technetate (+5), i.e. .sup.99m TcO(Undec)ema, in his doctoral thesis "Applications Of High-Pressure Liquid Chromatography In The Study Of Technetium Chemistry" submitted May, 1983, Massachusetts Institute of Technology. This compound was later tested for myocardial imaging in mice, however, a significant problem was encountered in the continuously high blood levels (6-8%/g) over the first 30 min, resulting in poor heart:blood ratios (0.8:1 at 5 min; 0.3:1 at 30 min). In addition, the relatively high kidney activity observed even at 5 min. post-injection suggests rapid metabolism to the TcO(ema).sup.-1 complex which is known to undergo rapid renal excretion.
Thus, a .sup.99m Tc-labelled ligand useful for studying the heart under aerobic physiological conditions is still being sought.